Identifying optimal vaccination scenarios to reduce varicella zoster virus transmission and reactivation

Background Varicella zoster virus (VZV) is one of the eight known human herpesviruses. Initial VZV infection results in chickenpox, while viral reactivation following a period of latency manifests as shingles. Separate vaccines exist to protect against both initial infection and subsequent reactivation. Controversy regarding chickenpox vaccination is contentious with most countries not including the vaccine in their childhood immunization schedule due to the hypothesized negative impact on immune-boosting, where VZV reactivation is suppressed through exogenous boosting of VZV antibodies from exposure to natural chickenpox infections. Methods Population-level chickenpox and shingles notifications from Thailand, a country that does not vaccinate against either disease, were previously fitted with mathematical models to estimate rates of VZV transmission and reactivation. Here, multiple chickenpox and shingles vaccination scenarios were simulated and compared to a model lacking any vaccination to analyze the long-term impacts of VZV vaccination. Results As expected, simulations suggested that an introduction of the chickenpox vaccine, at any coverage level, would reduce chickenpox incidence. However, chickenpox vaccine coverage levels above 35% would increase shingles incidence under realistic estimates of shingles coverage with the current length of protective immunity from the vaccine. A trade-off between chickenpox and shingles vaccination coverage was discovered, where mid-level chickenpox coverage levels were identified as the optimal target to minimize total zoster burden. Only in scenarios where shingles vaccine provided lifelong immunity or coverage exceeded current levels could large reductions in both chickenpox and shingles be achieved. Conclusions The complicated nature of VZV makes it impossible to select a single vaccination scenario as universal policy. Strategies focused on reducing both chickenpox and shingles incidence, but prioritizing the latter should maximize efforts towards shingles vaccination, while slowly incorporating chickenpox vaccination. Alternatively, countries may wish to minimize VZV complications of both chickenpox and shingles, which would lead to maximizing vaccine coverage levels across both diseases. Balancing the consequences of vaccination to overall health impacts, including understanding the impact of an altered mean age of infection for both chickenpox and shingles, would need to be considered prior to any vaccine introduction. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-022-02534-7.

where µ is the number of children born at time, t (treated as a known forcing function based on data). τ 11 represented the chickenpox vaccination rate. Below are the transitions for states E-L2; New infections for chickenpox at each time step were recorded as while new shingles infections were recorded as The above difference equations for each state are displayed in Fig 1,  where the fraction of those who remained in the susceptible state (pS) was modeled as where λ is the force of infection and δ is the death rate, which was assumed to be constant across all 18 model states and set for an average lifespan of 73 years [2]. The force of infection, λ was estimated as where β was the time-varying seasonal force of infection for chickenpox. I V Z was the number of current where β is the seasonal forcing for chickenpox and each ζ A is a periodic B-spline basis with 1 year period.

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β is summarized in table S1 as VZ splines 1-6. The fraction of those who remained in the exposed state 30 were modeled as where φ was a rate at which an individual became infectious after being exposed to chickenpox (parameter 32 scaled to 1/2 week). The fraction of those who remained in the infected with chickenpox state I V Z were 33 modeled as where γ was a fixed rate in which individuals recovered from chickenpox (parameter scaled to 7 days). The 35 fraction of those who remained in the first latent state, but remained susceptible to shingles reactivation 36 were modeled as where ι was a fixed parameter which represented the fraction of those infected with chickenpox that 38 would reactivate later in life as shingles (parameter scaled for a mean age 60 of years), κ is the seasonal 39 reactivation rate of shingles, and ψ is the time-varying immunity boosting from chickenpox infections (see 40 below for both κ and ψ model combinations, also Table S1 and Fig 2). κ was modeled as a B-spline, 41 similar to chickenpox: where each ζ B is a different (from ζ A ) B-spline basis with 1 year period. κ is summarized in table S1 43 as HZ splines 1-6. All parameters were estimated using maximum likelihood by iterated particle filtering 44 (MIF) in the R-package [9, 10].

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The fraction of those who remained infected with shingles were modeled as with the same recovery rate, γ (parameter scaled to 7 days), as chickenpox, while the fraction of those 47 who remained in the second latent state were modeled as where natural death was the only exit from the second latent state.

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The fraction of those who remained in the chickenpox vaccinated class was modeled as where ξ represented the length of immunity to chickenpox vaccination, which was set to 20 years [5].

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The fraction of those who remained in the shingles vaccinated class was modeled as where σ represented the length of immunity to shingles vaccination, which was set to either 5 years [6] 53 or lifetime.  Figure S1: Impact of chickenpox vaccination. (a) Chickenpox coverage is shown on the x-axis and the total reduction in chickenpox cases on the y-axis. The lines represent case reductions at 25 years (red), 50 years (black), 75 years (green), and 100 years (purple). (b) Percentage of additional chickenpox cases prevented by increasing coverage by 5% (that is, the rate of change in chickenpox reduction from (a). Dotted line at 5% identifies where you would achieve a greater than 5% reduction in cases for 5% additional coverage (above the line) and where you would achieve less than a 5% reduction in cases (below the dotted line). Table S2: Summary of the total cases over 100 years of all models against the null model lacking vaccination for chickenpox or shingles. ID is the model number correlating to Fig 1. Model ID is a quick reference to the model combinations explained in the next four columns. VZ Roll-out is the chickenpox vaccination coverage (slow -measles, moderate -hepatitis B, aggressive -Japanese Encephalitis), VZ uptake is the uptake level for the chickenpox vaccine, HZ coverage is the shingles vaccination coverage, and HZ immunity is the length of immunity provided by shingles vaccination. All models were compared to the number of cases with no chickenpox or shingles vaccination (top row). % of VZ cases is the percentage of chickenpox cases in that model scenario compared to the scenario without any vaccination over the entire 100 years (top row). % of HZ cases is the percentage of chickenpox cases in that model scenario compared to the scenario without any vaccination over the entire 100 years (top row   Figure S2: Percent of shingles cases by month of each model simulation compared to the null model with no vaccination (black). Models that offered no shingles vaccination or only 5-years of shingles immunity from vaccination, whether with perfect (red) or leaky (yellow) chickenpox uptake resulted in an increase in shingles cases compared to no vaccination at all. Lifetime shingles immunity from vaccination with low shingles coverage and perfect (green) or leaky (light blue) chickenpox uptake, resulted in reduced shingles cases. Lifetime shingles immunity paired with high shingles coverage rates with perfect (dark blue) or leaky (purple) chickenpox uptake resulted in the largest reduction in shingles cases.